7. The compound of claim 1 that comprises one or more mono-, di-, or
tri-phosphate groups.

8. The compound of claim 1 that comprises one or more mono-phosphate
groups.

9. The compound of claim 7 wherein the compound is a prodrug.

10. The compound of claim 7 wherein one or more phosphorous atoms of the
one or more pendent mono-, di-, or tri-phosphate groups is bonded to one
or more alkoxy or aryloxy groups.

11. The compound of claim 7 wherein one or more phosphorous atoms of the
pendent mono-, di-, or tri-phosphate groups is bonded to one or more
groups Ry--O--; wherein each Ry is independently a 1-20 carbon
branched or unbranched, saturated or unsaturated chain, wherein one or
more of the carbon atoms is optionally replaced with --O-- or --S-- and
wherein one or more of the carbon atoms is optionally substituted with
oxo (═O) or thioxo (═S).

12. The compound of claim 7 wherein one or more phosphorous atoms of the
one or more pendent mono-, di-, or tri-phosphate groups is bonded to one
or more groups Rz--N--; wherein each Rz is a residue of an
amino acid.

13. The compound of claim 12 wherein the amino acid is a natural amino
acid.

14. The compound of claim 7 which comprises one or more groups of formula:
##STR00062## wherein:R15 is H, alkyl, aryl, cycloalkyl, heteroaryl,
heterocyclic, or an amino acid;R16 is H, aryl, or heteroaryl; and
R17 is H, halogen, CN, --CO--R20, --CON(R21)2,
--CO2R20, --SO2R20, --SO2N(R21)2,
--OR21, --SR21, --R21, --N(R21)2,
--O--COR20, --O--CO2R20, --SCOR20,
--S--CO2R20, --NHCOR21, --NHCO2R21,
--(CH2)p--OR22, or --(CH2)p--SR22; or
R16 and R17 are connected via an additional 3-5 atoms to form a
cyclic group, optionally containing one heteroatom, that is fused to an
aryl group at the beta and gamma position to the O attached to the
phosphorus; or R17 and R18 are connected as described
below;R18 and R19 are each independently H, alkyl, aryl,
aralkyl, aryl, or heteroaryl; or R18 and R19 are connected via
an additional 2-5 atoms to form a cyclic group, optionally containing 0-2
heteroatoms; or R17 and R18 are connected via an additional 3-5
atoms to form a cyclic group, optionally containing one heteroatom and
R19 is H, alkyl, aryl, aralkyl, aryl or heteroaryl;R20 is
alkyl, aryl, or arylalkyl;R21 is H, alkyl, aryl, or
arylalkyl;R22 is H or lower acyl;p is an integer from 2-3;wherein
any alkyl, cycloalkyl, alkenyl, alkynyl, or acyl is optionally
substituted with 1 to 3 substituents selected from the group consisting
of alkoxy, acyl, acylamino, acyloxy, oxyacyl, amino, substituted amino,
aminoacyl, aryl, aryloxy, cyano, halogen, hydroxyl, nitro, N3,
carboxyl, carboxyl esters, thiol, thioalkyl, thioaryl, thioheteroaryl,
thiocycloalkyl, thioheterocyclic, cycloalkyl, heteroaryl, and
heterocyclic;and wherein any aryl, heteroaryl, or heterocycle is
optionally substituted with 1 to 3 substituents selected from the group
consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy,
oxyacyl, amino, substituted amino, aminoacyl, aryl, aryloxy, cyano,
halogen, hydroxyl, nitro, N3, carboxyl, carboxyl esters, thiol,
thioalkyl, thioaryl, thioheteroaryl, thiocycloalkyl, thioheterocyclic,
cycloalkyl, heteroaryl, and heterocyclic.

15. The compound of claim 1 which is a prodrug wherein one or more of
R2, R3, and R4 is acyloxy, acylamino or R--O; wherein R is
a carboxy-linked amino acid.

16. A pharmaceutical composition comprising a compound as described in
claim 1, or a pharmaceutically acceptable salt or prodrug thereof; and a
pharmaceutically acceptable carrier.

17. The composition of claim 16 which further comprises one or more
additional anti-viral agents, immune modulators, or interferon inducers.

18. The composition of claim 17 wherein the one or more anti-viral agents
are selected from ribavirin, levovirin, viramidine, thymosin alpha-1, an
inhibitor of a serine proteases, an inhibitor of inosine
monophosphatedehydrognease, interferon-.alpha., and pegylated
interferon-.alpha. (peginterferon-.alpha.).

19. The composition of claim 16 which further comprises one or more
additional HCV polymerase inhibitors.

20. The composition of claim 16 which further comprises one or more
protease inhibitors.

21. The composition of claim 16 which further comprises ribavirin.

22. The composition of claim 16 which further comprises interferon-.alpha.
or pegylated interferon-.alpha. (peginterferon-.alpha.).

34. The method of claim 23 wherein the compound of formula I comprises one
or more mono-, di-, or tri-phosphate groups.

35. The method of claim 23 wherein the compound of formula I comprises one
or more mono-phosphate groups.

36. The method of claim 34 wherein the compound is a prodrug.

37. The method of claim 34 wherein one or more phosphorous atoms of the
one or more pendent mono-, di-, or tri-phosphate groups is bonded to one
or more alkoxy or aryloxy groups.

38. The method of claim 34 wherein one or more phosphorous atoms of the
pendent mono-, di-, or tri-phosphate groups is bonded to one or more
groups Ry--O--; wherein each Ry is independently a 1-20 carbon
branched or unbranched, saturated or unsaturated chain, wherein one or
more of the carbon atoms is optionally replaced with --O-- or --S-- and
wherein one or more of the carbon atoms is optionally substituted with
oxo (═O) or thioxo (═S).

39. The method of claim 34 wherein one or more phosphorous atoms of the
one or more pendent mono-, di-, or tri-phosphate groups is bonded to one
or more groups Rz--N--; wherein each Rz is a residue of an
amino acid.

40. The method of claim 39 wherein the amino acid is a natural amino acid.

41. The method of claim 34 wherein the compound of formula I comprises one
or more groups of formula: ##STR00067## wherein:R15 is H, alkyl,
aryl, cycloalkyl, heteroaryl, heterocyclic, or an amino acid;R16 is
H, aryl, or heteroaryl; and R17 is H, halogen, CN, --CO--R20,
--CON(R21)2, --CO2R20, --SO2R20,
--SO2N(R21)2, --OR21, --SR21, --R21,
--N(R21)2, --O--COR20, --O--CO2R20,
--SCOR20, --S--CO2R20, --NHCOR21,
--NHCO2R21, --(CH2)p--OR22, or
--(CH2)p--SR22; or R16 and R17 are connected via
an additional 3-5 atoms to form a cyclic group, optionally containing one
heteroatom, that is fused to an aryl group at the beta and gamma position
to the O attached to the phosphorus; or R17 and R18 are
connected as described below;R18 and R19 are each independently
H, alkyl, aryl, aralkyl, aryl, or heteroaryl; or R18 and R19
are connected via an additional 2-5 atoms to form a cyclic group,
optionally containing 0-2 heteroatoms; or R17 and R18 are
connected via an additional 3-5 atoms to form a cyclic group, optionally
containing one heteroatom and R19 is H, alkyl, aryl, aralkyl, aryl
or heteroaryl;R20 is alkyl, aryl, or arylalkyl;R21 is H, alkyl,
aryl, or arylalkyl;R22 is H or lower acyl;p is an integer from
2-3;wherein any alkyl, cycloalkyl, alkenyl, alkynyl, or acyl is
optionally substituted with 1 to 3 substituents selected from the group
consisting of alkoxy, acyl, acylamino, acyloxy, oxyacyl, amino,
substituted amino, aminoacyl, aryl, aryloxy, cyano, halogen, hydroxyl,
nitro, N3, carboxyl, carboxyl esters, thiol, thioalkyl, thioaryl,
thioheteroaryl, thiocycloalkyl, thioheterocyclic, cycloalkyl, heteroaryl,
and heterocyclic;and wherein any aryl, heteroaryl, or heterocycle is
optionally substituted with 1 to 3 substituents selected from the group
consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy,
oxyacyl, amino, substituted amino, aminoacyl, aryl, aryloxy, cyano,
halogen, hydroxyl, nitro, N3, carboxyl, carboxyl esters, thiol,
thioalkyl, thioaryl, thioheteroaryl, thiocycloalkyl, thioheterocyclic,
cycloalkyl, heteroaryl, and heterocyclic.

42. The method of claim 33 wherein the prodrug is a compound of formula I
wherein one or more of R2, R3, and R4 is acyloxy,
acylamino or R--O; wherein R is a carboxy-linked amino acid.

43. The method of claim 23 which further comprises administering to the
animal one or more additional viral polymerase inhibitors.

44. The method claim 23 which further comprises administering to the
animal, one or more protease inhibitors.

45. The method of claim 23 which further comprises administering ribavirin
to the animal.

46. The method of claim 23 which further comprises administering
interferon-.alpha. or pegylated interferon-.alpha.
(peginterferon-.alpha.) to the animal.

47. The method of claim 27 wherein the virus is hepatitis C.

48. A method for inhibiting an HCV RNA or DNA polymerase comprising
contacting the polymerase in vitro or in vivo with an effective
inhibitory amount of a compound of formula I or a pharmaceutically
acceptable salt or prodrug thereof as described in claim 23.

Description:

RELATED APPLICATIONS

[0001]This application is a continuation of U.S. application Ser. No.
11/388,060, filed Mar. 23, 2006, and claims the benefit of priority to
International Application No. PCT/US2005/039072 filed Oct. 28, 2005; and
this application also claims the benefit of priority of U.S. Provisional
Application No. 60/665,832, filed Mar. 29, 2005 and the benefit of
priority of U.S. Provisional Application No. 60/692,572, filed Jun. 22,
2005; these applications are incorporated herein by reference in their
entirety.

BACKGROUND OF THE INVENTION

[0002]Viral diseases are a major cause of death and economic loss in the
world. The Flaviviridae family of viruses consists of three genera: the
flaviviruses (including dengue, West Nile, and yellow fever viruses),
hepacivirus (HCV), and the pestiviruses (including bovine viral diarrhea
virus, BVDV). The disease states and conditions caused by members of this
family include yellow fever, dengue, Japanese encephalitis, St. Louis
encephalitis, Hepatitis B and C, West Nile disease, and AIDS. Currently,
human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis
C virus (HCV) infections are responsible for the largest number of viral
related deaths worldwide. Although there are some drugs useful for
treating HIV, there are only a few drugs useful for treating HBV, and no
drugs that are broadly useful for treating HCV.

[0003]Ribavirin (1-β-D-ribofuranosyl-1-1,2,4-triazole-3-carboxamide)
is a synthetic, non-interferon-inducing, broad spectrum antiviral
nucleoside. Ribavirin is structurally similar to guanosine, and has in
vitro activity against several DNA and RNA viruses including Flaviviridae
(Davis. Gastroenterology 118:S104-S114, 2000). Ribavirin reduces serum
amino transferase levels to normal in 40% of patients, but it does not
lower serum levels of HCV-RNA. Thus, ribavirin alone is not effective in
reducing viral RNA levels. Additionally, ribavirin has significant
toxicity and is known to induce anemia.

[0004]Interferons (IFNs) are compounds which have been commercially
available for the treatment of chronic hepatitis for nearly a decade.
IFNs are glycoproteins produced by immune cells in response to viral
infection. IFNs inhibit viral replication of many viruses, including HCV.
When used as the sole treatment for hepatitis C infection, IFN suppresses
serum HCV-RNA to undetectable levels. Additionally, IFN normalizes serum
amino transferase levels. Unfortunately, the effects of IFN are temporary
and a sustained response occurs in only 8%-9% of patients chronically
infected with HCV (Davis. Gastroenterology 118:S104-S114, 2000).

[0005]HCV is a positive single stranded RNA virus with a well
characterized RNA-dependent RNA polymerase (RdRp) and a well
characterized disease progression. HCV has infected an estimated 170
million people worldwide, leading to a major health crisis as a result of
the disease. Indeed, during the next few years the number of deaths from
HCV-related liver disease and hepatocellular carcinoma may overtake those
caused by AIDS. Egypt is the hardest hit country in the world, with 23%
of the population estimated to be carrying the virus; whereas, in the USA
the prevalence of chronic infections has recently been determined to be
around 1.87% (2.7 million persons). HCV infections become chronic in
about 50% of cases. Of these, about 20% develop liver cirrhosis that can
lead to liver failure, including hepatocellular carcinoma.

[0006]The NS5B region of HCV encodes a 65 KDa RdRp thought to be
responsible for viral genome replication. RdRps function as the catalytic
subunit of the viral replicase required for the replication of all
positive-strand viruses. The NS5B protein has been well characterized,
shown to possess the conserved GDD motif of RdRps and in vitro assay
systems have been reported. Cellular localization studies revealed that
NS5B is membrane-associated in the endoplasmic reticulum like NS5A,
suggesting that those two proteins may remain associated with one another
after proteolytic processing. Additional evidence suggests that NS3, NS4A
and NS5B interact with each other to form a complex that functions as
part of the replication machinery of HCV.

[0007]The X-ray crystal structure of NS5B apoenzyme has been determined
and three very recent publications describe the unusual shape of the
molecule. This unique shape for a polymerase, resembling a flat sphere,
is attributed to extensive interactions between the fingers and thumb
subdomains in such a way that the active site is completely encircled,
forming a cavity 15 Å across and 20 Å deep. Modeling studies
showed that the NS5B apoenzyme can accommodate the template-primer
without large movement of the subdomains, suggesting that the structure
is preserved during the polymerization reaction. The RdRp polypeptides
from various members of the Flaviviridae family and other viral families
have been shown to be conserved (J. A. Bruenn, Nucleic Acids Research,
Vol. 19, No. 2 p. 217, 1991).

[0008]Viral diseases are one of the major causes of deaths and economic
losses in the world. Out of various viral diseases, HIV, HBV and HCV
infections are more important and responsible for a large number of
deaths. There are some drugs for HIV, only a few for HBV but no good drug
for HCV. Hepatitis C is a viral liver disease, caused by infection with
the hepatitis C virus (HCV). There are approximately 170 million people
worldwide with chronic HCV infection, of which about 2.7 million are in
the United States. HCV is a leading cause of cirrhosis, a common cause of
hepatocellular carcinoma, and is the leading cause of liver
transplantation in the United States. Currently, α-interferon
monotherapy and α-interferon-ribavirin combination therapy are the
only approved treatments for HCV.

[0009]U.S. Pat. No. 4,584,369 is directed to certain compounds that are
reported to inhibit the growth of leukemia cells. In the Background
section of the patent it states that some beta-glycosyl C-Nucleoside
compounds appear to have some anti-viral activity. There is no antiviral
data reported in the patent for any compounds and there is no disclosure
regarding which viruses the beta-glycosyl C-Nucleoside compounds may have
activity against.

SUMMARY OF THE INVENTION

[0010]It has been found that certain compounds inhibit a viral polymerase
from the Flaviviridae family of viruses, HCV viral polymerase.
Accordingly, the invention relates to certain fused furan, thiophene and
pyrrole compounds and particularly to fused furan, thiophene and pyrrole
compounds that are useful as inhibitors of hepatitis B, hepatitis C,
Polio, Coxsackie A and B, Rhino, Echo, small pox, Ebola, and West Nile
virus polymerases.

[0011]In one embodiment the invention provides a method for treating a
viral infection selected from hepatitis B, hepatitis C, Polio, Coxsackie
A and B, Rhino, Echo, small pox, Ebola, and West Nile in an animal (e.g.
a human), comprising administering to the animal an effective amount of a
compound of formula I:

[0020]R3, R4, R5, and R6 are independently selected
from the group consisting of H, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
heterocyclic, aryl, substituted aryl, acyl, substituted acyl,
SO2-alkyl OH, --COO-alkyl, CONH2, CONH-alkyl, O--C(O)-alkyl,
O--C(O)-aryl alkoxy and NO; or R3 and R4 together with the
nitrogen to which they are attached form a pyrrolidino, piperidino,
piperazino, azetidino, morpholino, pyrrolino, or thiomorpholino ring; or
R4 and R5 together with the nitrogen to which they are attached
form a pyrrolidino, piperidino, piperazino, azetidino, morpholino,
pyrrolino, or thiomorpholino ring; wherein any ring formed by R3 and
R4 or R4 and R5 is optionally substituted with one or more
hydroxyl, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, or substituted alkynyl; and

[0021]Ra, Rb, and Rc are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic,
aryl, acyl, SO2-alkyl and NO; or Ra and Rb together with
the nitrogen to which they are attached form a pyrrolidino, piperidino,
piperazino, azetidino, morpholino, pyrrolino, or thiomorpholino ring; or
Rb and Rc together with the nitrogen to which they are attached
form a pyrrolidino, piperidino, piperazino, azetidino, morpholino,
pyrrolino, or thiomorpholino ring;

[0022]or a pharmaceutically acceptable salt or prodrug thereof.

[0023]Certain compounds of formula I are novel. Accordingly, the invention
also provides novel compounds of formula I as described herein as well as
pharmaceutically acceptable salts and prodrugs thereof. For example, in
one embodiment, the invention provides a compound of the formula:

[0030]Ra, Rb, Rc, and Rd are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclic, aryl, acyl, SO2-alkyl and NO; or Ra and Rb
together with the nitrogen to which they are attached form a pyrrolidino,
piperidino, piperazino, azetidino, morpholino, pyrrolino, or
thiomorpholino ring; or Rb and Rc together with the nitrogen to
which they are attached form a pyrrolidino, piperidino, piperazino,
azetidino, morpholino, pyrrolino, or thiomorpholino ring;

[0031]Re is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl,
acyl, SO2-alkyl or NO; and Rf is H, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclic, aryl, acyl, SO2-alkyl and NO; or Re
and Rf together with the nitrogen to which they are attached form a
pyrrolidino, piperidino, piperazino, azetidino, morpholino, pyrrolino, or
thiomorpholino ring; which ring is optionally substituted with one or
more halo, hydroxyl, alkyl, alkenyl, or alkynyl;

[0035]In another embodiment the invention provides a method for inhibiting
an HCV RNA or DNA polymerase comprising contacting the polymerase in
vitro or in vivo with an effective inhibitory amount of a compound of
formula I or a pharmaceutically acceptable salt or prodrug thereof.

[0036]In another embodiment the invention provides a pharmaceutical
composition comprising a compound of formula I or a pharmaceutically
acceptable salt or prodrug thereof; and a pharmaceutically acceptable
carrier. The composition can optionally comprise one or more additional
anti-viral agents, immune modulators, or interferon inducers.

[0037]In another embodiment the invention provides a method for treating
hepatitis C in an animal comprising administering to the animal an
effective amount of a compound of formula I, or a pharmaceutically
acceptable salt or prodrug thereof.

[0038]In another embodiment the invention provides a method for inhibiting
an HCV RNA or DNA polymerase comprising contacting the polymerase (in
vitro or in vivo) with an effective inhibitory amount of a compound of
formula I, or a pharmaceutically acceptable salt or prodrug thereof.

[0040]The terms "treat", "treating" and "treatment" as used herein include
administering a compound prior to the onset of clinical symptoms of a
disease state/condition so as to prevent any symptom, as well as
administering a compound after the onset of clinical symptoms of a
disease state/condition so as to reduce or eliminate any symptom, aspect
or characteristic of the disease state/condition. Such treating need not
be absolute to be useful.

[0041]The term "animal" as used herein refers to any animal, including
mammals, such as, but not limited to, mice, rats, other rodents, rabbits,
dogs, cats, swine, cattle, sheep, horses, and primates. In one specific
embodiment of the invention the animal is a human.

[0042]The term "therapeutically effective amount", in reference to
treating a disease state/condition, refers to an amount of a compound
either alone or as contained in a pharmaceutical composition that is
capable of having any detectable, positive effect on any symptom, aspect,
or characteristics of a disease state/condition when administered as a
single dose or in multiple doses. Such effect need not be absolute to be
beneficial.

[0043]The term "alkyl" as used herein refers to alkyl groups having from 1
to 6 carbon atoms. This term is exemplified by groups such as methyl,
ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl and the like. In
a specific embodiment, the alkyl groups have from 1-4 carbon atoms and
are referred to as lower alkyl.

[0044]The terms "alkenyl" or "alkene" as used herein refers to an alkenyl
group having from 2 to 10 carbon atoms and having at least 1 site of
alkenyl unsaturation. Such groups are exemplified by vinyl(ethen-1-yl),
allyl, but-3-en-1-yl, and the like.

[0045]The term "alkynyl" or "alkyne" as used herein refers to an alkynyl
group having from 2-10 carbon atoms and having at least 1 site of alkynyl
unsaturation. Such groups are exemplified by, but not limited to,
ethyn-1-yl, propyn-1-yl, propyn-2-yl, 1-methylprop-2-yn-1-yl, butyn-1-yl,
butyn-2-yl, butyn-3-yl, and the like.

[0046]The term "alkoxy" refers to the group alkyl-O--.

[0047]The term "acyl" as used herein refers to the groups alkyl-C(O)--,
alkenyl-C(O)--, alkynyl-C(O) cycloalkyl-C(O)--, aryl-C(O)--,
heteroaryl-C(O)--, and heterocyclic-C(O).

[0048]The term "acylamino" as used herein refers to the group
--C(O)NZ1Z2 where each Z1 and Z2 are independently
selected from the group consisting of hydrogen, alkyl, alkenyl, and
alkynyl.

[0049]The term "acyloxy" as used herein refers to the groups
alkyl-C(O)O--, alkenyl-C(O)O--, alkynyl-C(O)O--, aryl-C(O)O--,
cycloalkyl-C(O)O--, heteroaryl-C(O)O--, and heterocyclic-C(O)O--.

[0050]The term "oxyacyl" as used herein refers to the groups
alkyl-OC(O)--, alkenyl-OC(O)--, alkynyl-OC(O) aryl-OC(O)--,
cycloalkyl-OC(O)--, heteroaryl-OC(O)--, and heterocyclic-OC(O)--.

[0051]The term "amino" as used herein refers to the group --NH2.

[0052]The term "substituted amino" as used herein refers to the group
--NZ1Z2 where Z1 and Z2 are as described above in the
definition of acylamino, provided that Z1 and Z2 are both not
hydrogen.

[0053]The term "aminoacyl" as used herein refers to the groups
--NZ3C(O)alkyl, --NZ3C(O)cycloalkyl, --NZ3C(O)alkenyl,
--NZ3C(O)alkynyl, --NZ3C(O)aryl, --NZ3C(O)heteroaryl, and
--NZ3C(O)heterocyclic, where Z3 is hydrogen or alkyl.

[0054]The term "aryl" as used herein refers to a monovalent aromatic
cyclic group of from 6 to 14 carbon atoms having a single ring (e.g.,
phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which
condensed rings may or may not be aromatic. Exemplary aryls include, but
are not limited to, phenyl and naphthyl.

[0055]The term "aryloxy" as used herein refers to the group aryl-O-- that
includes, by way of example but not limitation, phenoxy, naphthoxy, and
the like.

[0056]The term "carboxyl" as used herein refers to --COOH or salts
thereof.

[0057]The term "carboxyl esters" as used herein refers to the groups
--C(O)O-alkyl, and --C(O)O-aryl.

[0058]The term "cycloalkyl" as used herein refers to a saturated or
unsaturated cyclic hydrocarbon ring systems, such as those containing 1
to 3 rings and 3 to 7 carbons per ring. Exemplary groups include but are
not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and adamantyl.

[0059]The term "cycloalkoxy" as used herein refers to --O-cycloalkyl
groups.

[0060]The term "formyl" as used herein refers to HC(O)--.

[0061]The term "halogen" as used herein refers to fluoro, chloro, bromo
and iodo.

[0062]The term "heteroaryl" as used herein refers to an aromatic group of
from 5 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group
consisting of oxygen, nitrogen, sulfur in the ring. The sulfur and
nitrogen heteroatoms atoms may also be present in their oxidized forms.
Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or
multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the
condensed rings may or may not be aromatic and/or contain a heteroatom.
Exemplary heteroaryl groups include, but are not limited to, heteroaryls
include pyridyl, pyrrolyl, thienyl, indolyl, thiophenyl, and furyl.

[0063]The term "heteroaryloxy" as used herein refers to the group
--O-heteroaryl.

[0064]The term "heterocycle" or "heterocyclic" refers to a saturated or
unsaturated group (but not heteroaryl) having a single ring or multiple
condensed rings, from 3 to 10 carbon atoms and from 1 to 4 hetero atoms
selected from the group consisting of nitrogen, oxygen, sulfur, within
the ring wherein, in fused ring systems, one or more the rings can be
cycloalkyl, aryl or heteroaryl provided that the point of attachment is
through the heterocyclic ring. The sulfur and nitrogen atoms may also be
present in their oxidized forms.

[0066]The term "phosphate" as used herein refers to the groups
--OP(O)(OH)2 (monophosphate or phospho), --OP(O)(OH)OP(O)(OH)2
(diphosphate or diphospho) and --OP(O)(OH)OP(O)(OH)OP(O)(OH)2
(triphosphate or triphospho) or salts thereof including partial salts
thereof. It is understood that the initial oxygen of the mono-, di-, and
triphosphate may include the oxygen atom of a sugar.

[0067]The term "phosphate esters" as used herein refers to the mono-, di-
and tri-phosphate groups described above wherein one or more of the
hydroxyl groups is replaced by an alkoxy group.

[0073]The term "substituted aryl" as used herein refers to aryl groups
which are substituted with from 1 to 3 substituents selected from alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted
alkynyl, and those substituents described above in the definition of
substituted alkyl.

[0074]The term "substituted aryloxy" as used herein refers to substituted
aryl-O-- groups.

[0075]The term "substituted cycloalkyl" as used herein refers to a
cycloalkyl having from 1 to 5 substituents selected from the group
consisting of oxo (═O), thioxo (═S), alkyl, substituted alkyl,
and those substituents described in the definition of substituted alkyl.

[0076]The term "substituted cycloalkoxy" as used herein refers to --O--
substituted cycloalkyl groups.

[0077]The term "substituted heteroaryl" as used herein refers to
heteroaryl groups that are substituted with from 1 to 3 substituents
selected from the same group of substituents defined for substituted
aryl.

[0078]The term "substituted heteroaryloxy" as used herein refers to the
group --O-- substituted heteroaryl.

[0079]The term "substituted heterocycle" or "substituted heterocyclic" or
"substituted heterocycloalkyl" refers to heterocycle groups that are
substituted with from 1 to 3 of the same substituents as defined for
substituted aryl.

[0080]The term "thiol" as used herein refers to the group --SH.

[0081]The term "thioalkyl" or "alkylthioether" or "thioalkoxy" refers to
the group --S-alkyl.

[0082]The term "thiocycloalkyl" as used herein refers to the group
--S-cycloalkyl.

[0083]The term "thioaryl" as used herein refers to the group --S-aryl.

[0084]The term "thioheteroaryl" as used herein refers to the group
--S-heteroaryl.

[0085]The term "thioheterocyclic" as used herein refers to the group --S--
heterocyclic.

[0086]The term "amino acid sidechain" refers to the Z7 substituent of
α-amino acids of the formula Z6NHCH(Z7)COOH where Z7
is selected from the group consisting of hydrogen, alkyl, and aryl and
Z6 is hydrogen or together with Z7 and the nitrogen and carbon
atoms bound thereto respectively form a heterocyclic ring. In one
embodiment, the α-amino acid sidechain is the sidechain one of the
twenty naturally occurring L amino acids.

[0087]Sugars described herein may either be in D or L configuration.

[0088]Specific values listed below for radicals, substituents, and ranges,
are for illustration only; they do not exclude other defined values or
other values within defined ranges for the radicals and substituents

[0089]A specific value for R is ORa, Cl, SRa, NReRf,
aryl or NRaNRbRc; wherein Ra, Rb, Rc, and
Rd are independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, acyl, SO2-alkyl
and NO; or Rb and Rc together with the nitrogen to which they
are attached form a pyrrolidino, piperidino, piperazino, azetidino,
morpholino, pyrrolino, or thiomorpholino ring; Re is alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclic, aryl, acyl, SO2-alkyl or NO; and
Rf is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl,
acyl, SO2-alkyl and NO; or Re and Rf together with the
nitrogen to which they are attached form a pyrrolidino, piperidino,
piperazino, azetidino, morpholino, pyrrolino, or thiomorpholino ring;
which ring is optionally substituted with one or more halo, hydroxyl,
alkyl, alkenyl, or alkynyl.

[0093]In one embodiment, the invention excludes compounds of formula I
wherein Y is S; when R is --NH2, --OH, --SH, or --SCH3; R1
is hydrogen; and R2 is non-phosphorylated ribose; as well as
compounds of formula I wherein Y is O; when R is --NH2; R1 is
hydrogen; and R2 is non-phosphorylated ribose.

[0094]In another embodiment the invention excludes compounds of formula I
wherein Y is S; R is --NH2, --OH, --SH, or --SCH3; R1 is
hydrogen; and R2 is ribose; as well as compounds of formula I
wherein Y is O; R is --NH2; R1 is hydrogen; and R2 is
ribose. In another embodiment, the invention excludes compounds of
formula I wherein R is --SH, --OH, --S-alkyl, --O-alkyl, or
NR3R4; R3 and R4 are each H or alkyl; and R2 has
the following formula:

##STR00003##

wherein: one of R300 and R304 is H and the other is H or OH;
R302 is OH, alkyl-O--, alkylC(═O)O--, alkyl-S--, or
alkylC(═O)--S--; R303 is H; and Z300 is OH, alkyl-O--,
alkylC(═O)O--, alkyl-S--, or alkylC(═O)--S--.

[0095]In another embodiment, the invention excludes compounds of formula I
wherein R2 has the following formula:

##STR00004##

wherein: one of R300 and R304 is H and the other is H or OH;
R302 is OH, alkyl-O--, alkylC(═O)O, alkyl-S--, or
alkylC(═O)--S--; R303 is H; and Z300 is OH, alkyl-O--,
alkylC(═O)O, alkyl-S--, or alkylC(═O)--S--.

[0096]In one embodiment of the invention R2 is:

##STR00005##

[0097]In one embodiment of the invention R2 is:

##STR00006##

[0098]In one embodiment of the invention R2 is:

##STR00007##

[0099]In one embodiment of the invention R3 is H.

[0100]In one embodiment of the invention the compound of formula I has the
following formula:

[0106]R3, R4, R5, and R6 are independently selected
from the group consisting of H, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
heterocyclic, aryl, substituted aryl, acyl, substituted acyl,
SO2-alkyl and NO; or R3 and R4 together with the nitrogen
to which they are attached form a pyrrolidino, piperidino, piperazino,
azetidino, morpholino, or thiomorpholino ring; or R4 and R5
together with the nitrogen to which they are attached form a pyrrolidino,
piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring;

[0107]or a pharmaceutically acceptable salt or prodrug thereof.

[0108]In one embodiment of the invention the compound of formula I has the
formula:

[0123]R5 is OH, alkyl-O--, alkylC(═O)O, alkyl-S--, or
alkylC(═O)--S--Ra, Rb, Rc, and Rd are
independently selected from the group consisting of H, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclic, aryl, acyl, SO2-alkyl and NO; or
Ra and Rb together with the nitrogen to which they are attached
form a pyrrolidino, piperidino, piperazino, azetidino, morpholino,
pyrrolino, or thiomorpholino ring; or Rb and Rc together with
the nitrogen to which they are attached form a pyrrolidino, piperidino,
piperazino, azetidino, morpholino, pyrrolino, or thiomorpholino ring;

[0124]Re is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl,
acyl, SO2-alkyl or NO; and Rf is H, alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclic, aryl, acyl, SO2-alkyl and NO; or Re
and Rf together with the nitrogen to which they are attached form a
pyrrolidino, piperidino, piperazino, azetidino, morpholino, pyrrolino, or
thiomorpholino ring; which ring is optionally substituted with one or
more halo, hydroxyl, alkyl, alkenyl, or alkynyl;

[0127]The term "prodrug" as used herein refers to a compound that can be
metabolized in vivo to provide a compound of formula I. Thus prodrugs
include compounds that can be prepared by modifying one or more
functional groups in a compound of formula I to provide a corresponding
compound that can be metabolized in vivo to provide a compound of formula
I. Such modifications are known in the art. For example, one or more
hydroxy groups or amine groups in a compound of formula I can be acylated
with alkyl-C(═O)-- groups or with residues from amino acids to
provide a prodrug. Alternatively, one or more pendent hydroxyl groups
from a mono-, di-, or tri-phosphate functionality in a compound of
formula I can be converted to an alkoxy, or aryloxy group.

[0128]In one embodiment, the term prodrug includes a compound wherein one
or more hydroxy groups on a nucleoside sugar group (e.g. a 2', 3', or 5'
hydroxy group) have been converted to a group that can be metabolized in
vivo to provide a compound of formula I. For example, the invention
provides a compound wherein one or more hydroxy groups on a nucleoside
sugar group (e.g. a 2', 3', or 5' hydroxy group) have been converted to
an acyloxy, acylamino or R--O group, wherein R is a carboxy-linked amino
acid.

[0129]In one embodiment, the term prodrug includes a compound wherein one
or more pendent hydroxyl groups from a mono-, di-, or tri-phosphate
functionality in a compound of formula I is converted to a group
Ry--O--; wherein each Ry is independently a 1-20 carbon
branched or unbranched, saturated or unsaturated chain, wherein one or
more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced with
--O-- or --S-- and wherein one or more of the carbon atoms is optionally
substituted with oxo (═O) or thioxo (═S) (See Lefebvre et al., J.
Med. Chem. 1995, 38, 3941-50).

[0130]In another embodiment, the term prodrug includes a compound wherein
one or more pendent hydroxyl groups from a mono-, di-, or tri-phosphate
functionality in a compound of formula I is converted to a group
Rz--N--; wherein each Rz is a residue of an amino acid. Thus,
in the methods of treatment of the present invention, the term
"administering" includes administration of a compound of formula I, as
well as administration of a prodrug which converts to a compound of
formula I or a salt thereof in vivo. Conventional procedures for the
selection and preparation of prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985; and
in International Patent Application Publication Number WO 2005/084192. A
variety of prodrugs are also described in International Patent
Application Number PCT US2004/013063, which was published as
International Publication Number WO 2004/096286.

[0131]In another embodiment the prodrug comprises one of more groups of
formula:

[0133]R16 is H, monocyclic aryl, or monocyclic heteroaryl; and
R17 is H, halogen, CN, --CO--R20, --CON(R21)2,
--CO2R20, --SO2R20, --SO2N(R21)2,
--OR21, --SR21, --R21, --N(R21)2,
--O--COR20, --O--CO2R20, --SCOR20,
--S--CO2R20, --NHCOR21, --NHCO2R21,
--(CH2)p--OR22, or --(CH2)p--SR22; or
R16 and R17 are connected via an additional 3-5 atoms to form a
cyclic group, optionally containing one heteroatom, that is fused to an
aryl group at the beta and gamma position to the O attached to the
phosphorus; or R17 and R18 are connected as described below;

[0134]R18 and R19 are each independently H, alkyl, aryl,
aralkyl, monocyclic aryl or monocyclic heteroaryl; or R18 and
R19 are connected via an additional 2-5 atoms to form a cyclic
group, optionally containing 0-2 heteroatoms; or R17 and R18
are connected via an additional 3-5 atoms to form a cyclic group,
optionally containing one heteroatom and R19 is H, alkyl, aryl,
aralkyl, monocyclic aryl or monocyclic heteroaryl; and

[0149](--CO2Rm) where the Rm group corresponds to any
alcohol whose release in the body through enzymatic or hydrolytic
processes would be at pharmaceutically acceptable levels. Another prodrug
derived from a carboxylic acid form of the disclosure may be a quaternary
salt type of structure described by Bodor et al., J. Med. Chem. 1980, 23,
469.

##STR00012##

Synthetic Processes

[0150]Processes for preparing compounds of formula I, or pharmaceutically
acceptable salts or prodrugs thereof, as well as processes for preparing
intermediate compounds that can be used to prepare compounds of formula I
or pharmaceutically acceptable salts or prodrugs thereof are provided as
further embodiments of the invention. For example in one embodiment the
invention provides a method for preparing a pharmaceutically acceptable
salt of compound of formula I comprising converting a corresponding
compound of formula I to the salt.

[0151]In another embodiment the invention provides a method for preparing
a prodrug of a compound of formula I comprising converting a
corresponding compound of formula I to the prodrug.

[0152]In another embodiment the invention provides a method for preparing
a compound of formula I, comprising deprotecting a corresponding compound
of formula I that comprises one or more protecting groups to provide the
compound of formula I.

Isomers and Physical Forms

[0153]It will be appreciated by those skilled in the art that compounds of
the invention having a chiral center may exist in and be isolated in
optically active and racemic forms. Some compounds may exhibit
polymorphism. It is to be understood that the present invention
encompasses any racemic, optically-active, polymorphic, tautomeric, or
stereoisomeric form, or mixtures thereof, of a compound of the invention
(e.g. a compound of formula I), which possess the useful properties
described herein, it being well known in the art how to prepare optically
active forms (for example, by resolution of the racemic form by
recrystallization techniques, by synthesis from optically-active starting
materials, by chiral synthesis, or by chromatographic separation using a
chiral stationary phase) and how to determine anti-viral activity using
the standard tests described herein, or using other similar tests which
are well known in the art. Although the invention includes all isomeric
forms of the compounds described herein, one embodiment of the invention
provides compounds having the absolute stereochemistry depicted in the
Examples hereinbelow.

[0154]It will be appreciated that sugars can exist in α- and
β-forms. The invention includes compounds of formula I comprising
sugars in both α- and β-forms. In one embodiment, the sugars
are in the C-1β-form.

[0155]For example, it would be known in the field of chemistry that a
compound of the following formula:

##STR00013##

wherein R is OH would form a tautomer of the following formula:

##STR00014##

Accordingly, the invention includes all tautomeric forms of the compounds
of formulae I.

Pharmaceutical Compositions, Modes of Administration and Methods of
Treatment

[0156]The present disclosure provides compounds of the general formula (I)
as detailed above which are inhibitors of HCV DNA and/or RNA polymerases.
Various forms of DNA and RNA viral polymerases are inhibited by the
compounds disclosed, such as but not limited to HCV RdRps. The compounds
of the present disclosure therefore have utility in treating and/or
preventing HCV infections in a host and in treatment and/or preventing a
variety of disease states and/or conditions caused by or related to HCV
infections. In one embodiment, the compounds are useful in the above
mentioned treating and/or preventing by inhibiting a HCV RNA and DNA
polymerases.

[0157]The pharmaceutically acceptable carriers described herein,
including, but not limited to, vehicles, adjuvants, excipients, or
diluents, are well-known to those who are skilled in the art. Typically,
the pharmaceutically acceptable carrier is chemically inert to the active
compounds and has no detrimental side effects or toxicity under the
conditions of use. The pharmaceutically acceptable carriers can include
polymers and polymer matrices.

[0158]The compounds described in the instant disclosure can be
administered by any conventional method available for use in conjunction
with pharmaceuticals, either as individual therapeutic agents or in
combination with additional therapeutic agents.

[0159]The compounds described are administered in a pharmaceutically
effective amount. The pharmaceutically effective amount of the compound
and the dosage of the pharmaceutical composition administered will, of
course, vary depending upon known factors, such as the pharmacodynamic
characteristics of the particular agent and its mode and route of
administration; the age, health and weight of the recipient; the severity
and stage of the disease state or condition; the kind of concurrent
treatment; the frequency of treatment; and the effect desired.

[0160]A daily dosage of active ingredient can be expected to be about
0.001 to 1000 milligrams (mg) per kilogram (kg) of body weight per day.
In one embodiment, the total amount is between about 0.1 mg/kg and about
100 mg/kg of body weight per day; in an alternate embodiment between
about 1.1 mg/kg and about 50 mg/kg of body weight per day; in yet another
alternate embodiment between 0.1 mg/kg and about 30 mg/kg of body weight
per day. The above described amounts may be administered as a series of
smaller doses over a period of time if desired. The pharmaceutically
effective amount can be calculated based on the weight of the parent
compound to be delivered. If the salt or prodrug exhibits activity in
itself, the pharmaceutically effective amount can be estimated as above
using the weight of the salt or prodrug, or by other means known to those
skilled in the art. The dosage of active ingredient may be given other
than daily if desired.

[0161]The total amount of the compound administered will also be
determined by the route, timing and frequency of administration as well
as the existence, nature, and extent of any adverse side effects that
might accompany the administration of the compound and the desired
physiological effect. It will be appreciated by one skilled in the art
that various conditions or disease states, in particular chronic
conditions or disease states, may require prolonged treatment involving
multiple administrations.

[0162]Dosage forms of the pharmaceutical compositions described herein
(forms of the pharmaceutical compositions suitable for administration)
contain from about 0.1 mg to about 3000 mg of active ingredient (i.e. the
compounds disclosed) per unit. In these pharmaceutical compositions, the
active ingredient will ordinarily be present in an amount of about
0.5-95% weight based on the total weight of the composition. Multiple
dosage forms may be administered as part of a single treatment. The
active ingredient may be administered to achieve peak plasma
concentrations of the active ingredient of from about 0.2 to 70 μM, or
from about 1.0 to 10 μM.

[0163]The active ingredient can be administered orally in solid dosage
forms, such as capsules, tablets, and powders, or in liquid dosage forms,
such as elixirs, syrups and suspensions. It can also be administered
parenterally, in sterile liquid dosage forms. The active ingredient can
also be administered intranasally (nose drops) or by inhalation via the
pulmonary system, such as by propellant based metered dose inhalers or
dry powders inhalation devices. Other dosage forms are potentially
possible such as administration transdermally, via patch mechanisms or
ointment.

[0164]Formulations suitable for oral administration can include (a) liquid
solutions, such as a pharmaceutically effective amount of the compound
dissolved in diluents, such as water, saline, or orange juice; (b)
capsules, sachets, tablets, lozenges, and troches, each containing a
predetermined pharmaceutically effective amount of the active ingredient,
as solids or granules; (c) powders; (d) suspensions in an appropriate
liquid; and (e) suitable emulsions. Liquid formulations may include
diluents, such as water and alcohols, for example, ethanol, benzyl
alcohol, propylene glycol, glycerin, and the polyethylene alcohols,
either with or without the addition of a pharmaceutically acceptable
surfactant, suspending agent, or emulsifying agent. Capsule forms can be
of the ordinary hard- or soft-shelled gelatin type containing, for
example, surfactants, lubricants, and inert fillers, such as lactose,
sucrose, calcium phosphate, and corn starch. Tablet forms can include one
or more of the following: lactose, sucrose, mannitol, corn starch, potato
starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar
gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium
stearate, calcium stearate, zinc stearate, stearic acid, and other
excipients, colorants, diluents, buffering agents, disintegrating agents,
moistening agents, preservatives, flavoring agents, and pharmacologically
compatible carriers. Lozenge forms can comprise the active ingredient in
a flavor, usually sucrose and acacia or tragacanth, as well as pastilles
comprising the active ingredient in an inert base, such as gelatin and
glycerin, or sucrose and acadia, emulsions, and gels containing, in
addition to the active ingredient, such carriers as are known in the art.

[0165]Formulations suitable for parenteral administration include aqueous
and non-aqueous, isotonic sterile injection solutions, which can contain
anti-oxidants, buffers, bacteriostats, and solutes that render the
formulation isotonic with the blood of the patient, and aqueous and
non-aqueous sterile suspensions that can include suspending agents,
solubilizers, thickening agents, stabilizers, and preservatives. The
compound can be administered in a physiologically acceptable diluent in a
pharmaceutically acceptable carrier, such as a sterile liquid or mixture
of liquids, including water, saline, aqueous dextrose and related sugar
solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl
alcohol, glycols, such as propylene glycol or polyethylene glycol such as
poly(ethyleneglycol) 400, glycerol ketals, such as
2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, an oil, a fatty acid, a
fatty acid ester or glyceride, or an acetylated fatty acid glyceride with
or without the addition of a pharmaceutically acceptable surfactant, such
as a soap or a detergent, suspending agent, such as pectin, carbomers,
methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose,
or emulsifying agents and other pharmaceutical adjuvants.

[0167]The parenteral formulations typically contain from about 0.5% to
about 25% by weight of the active ingredient in solution. Suitable
preservatives and buffers can be used in such formulations. In order to
minimize or eliminate irritation at the site of injection, such
compositions may contain one or more nonionic surfactants having a
hydrophile-lipophile balance (HLB) of from about 12 to about 17. The
quantity of surfactant in such formulations ranges from about 5% to about
15% by weight. Suitable surfactants include polyethylene sorbitan fatty
acid esters, such as sorbitan monooleate and the high molecular weight
adducts of ethylene oxide with a hydrophobic base, formed by the
condensation of propylene oxide with propylene glycol.

[0168]Pharmaceutically acceptable excipients are also well-known to those
who are skilled in the art. The choice of excipient will be determined in
part by the particular compound, as well as by the particular method used
to administer the composition. Accordingly, there is a wide variety of
suitable formulations of the pharmaceutical composition of the present
invention. The following methods and excipients are merely exemplary and
are in no way limiting. The pharmaceutically acceptable excipients
preferably do not interfere with the action of the active ingredients and
do not cause adverse side-effects. Suitable carriers and excipients
include solvents such as water, alcohol, and propylene glycol, solid
absorbants and diluents, surface active agents, suspending agent,
tableting binders, lubricants, flavors, and coloring agents.

[0169]The compounds of the present invention, alone or in combination with
other suitable components, can be made into aerosol formulations to be
administered via inhalation. These aerosol formulations can be placed
into pressurized acceptable propellants, such as dichlorodifluoromethane,
propane, and nitrogen. Such aerosol formulations may be administered by
metered dose inhalers. They also may be formulated as pharmaceuticals for
non-pressured preparations, such as in a nebulizer or an atomizer.

[0170]The formulations can be presented in unit-dose or multi-dose sealed
containers, such as ampules and vials, and can be stored in a
freeze-dried (lyophilized) condition requiring only the addition of the
sterile liquid excipient, for example, water, for injections, immediately
prior to use. Extemporaneous injection solutions and suspensions can be
prepared from sterile powders, granules, and tablets. The requirements
for effective pharmaceutically acceptable carriers for injectable
compositions are well known to those of ordinary skill in the art. See
Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia,
Pa., Banker and Chalmers, Eds., 238-250 (1982) and ASHP Handbook on
Injectable Drugs, Toissel, 4th ed., 622-630 (1986).

[0171]Formulations suitable for topical administration include pastilles
comprising the active ingredient in an inert base, such as gelatin and
glycerin, or sucrose and acacia, as well as creams, emulsions, and gels
containing, in addition to the active ingredient, such carriers as are
known in the art. Furthermore, transdermal patches can be prepared using
methods known in the art.

[0172]Additionally, formulations suitable for rectal administration may be
presented as suppositories by mixing with a variety of bases such as
emulsifying bases or water-soluble bases. Formulations suitable for
vaginal administration may be presented as pessaries, tampons, creams,
gels, pastes, foams, or spray formulas containing, in addition to the
active ingredient, such carriers as are known in the art to be
appropriate.

[0173]One skilled in the art will appreciate that suitable methods of
administering a compound of the present invention to an patient are
available, and, although more than one route can be used to administer a
particular compound, a particular route can provide a more immediate and
more effective reaction than another route.

[0174]Useful embodiments of pharmaceutical dosage forms for administration
of the compounds according to the present invention can be illustrated as
follows.

[0175]A large number of hard-shell capsules are prepared by filling
standard two-piece hard gelatine capsules each with 100 mg of powdered
active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of
magnesium stearate.

[0176]A mixture of active ingredient in a digestible oil such as soybean
oil, cottonseed oil or olive oil is prepared and injected by means of a
positive displacement pump into molten gelatin to form soft gelatin
capsules containing 100 mg of the active ingredient. The capsules are
washed and dried. The active ingredient can be dissolved in a mixture of
polyethylene glycol, glycerin and sorbitol to prepare a water miscible
medicine mix.

[0177]A large number of tablets are prepared by conventional procedures so
that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal
silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline
cellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate aqueous
and non-aqueous coatings may be applied to increase palatability, improve
elegance and stability or delay absorption.

[0178]Immediate release tablets/capsules are solid oral dosage forms made
by conventional and novel processes. These units are taken orally without
water for immediate dissolution and delivery of the medication. The
active ingredient is mixed in a liquid containing ingredient such as
sugar, gelatin, pectin and sweeteners. These liquids are solidified into
solid tablets or caplets by freeze drying and solid state extraction
techniques. The drug compounds may be compressed with viscoelastic and
thermoelastic sugars and polymers or effervescent components to produce
porous matrices intended for immediate release, without the need of
water.

[0179]Moreover, the compounds of the present invention can be administered
in the form of nose drops, or metered dose and a nasal or buccal inhaler.
The drug is delivered from a nasal solution as a fine mist or from a
powder as an aerosol.

[0180]In one embodiment, the teachings of the present disclosure provide
for the use of such pharmaceutical compositions and medicaments in a
method of treating a HCV infection or treating a disease state and/or
condition caused by or related to such infection. Such treatment need not
be complete to be useful.

[0181]The methods of treating HCV infection or a disease state and/or
condition caused by or related to said infection may further comprise
administering a therapeutically effective amount of a compound of the
present invention in combination with a therapeutically effective amount
of an immune modulator, an interferon inducer (see Kurimoto et. al.
Bioorganic and Med. Chem., 2003, 11, 5501-5508; and Hirota et. al. J.
Med. Chem. 2002, 45, 5419-5422), or another anti-viral agent which, in
particular, may be active against HCV. Agents active against HCV include,
but are not limited to, ribavirin, levovirin, viramidine, thymosin
alpha-1, an inhibitor of HCV NS3 serine protease, an inhibitor of inosine
monophosphate-dehydrognease, interferon-α, pegylated
interferon-α (peginterferon-α), a combination of
interferon-α and ribavirin, a combination of peginterferon-α
and ribavirin, a combination of interferon-α and levovirin, and a
combination of peginterferon-α and levovirin. Interferon-α
includes, but is not limited to, recombinant interferon-α2α,
interferon-α2b, a consensus interferon, and a purified
interferon-α product.

[0182]The ability of a compound to inhibit an HCV polymeras can be
evaluated using known assays. The ability of a compound to inhibit HCV
NS5B polymerase can be evaluated using the following assay.

HCV NS5B Polymerase Assay

[0183]Antiviral activity of the test compounds can be assessed (Okuse et
al., Antiviral Res. 2005, 65, 23-34) in the stably HCV RNA-replicating
cell line, AVA5, derived by transfection of the human hepatoblastoma cell
line, Huh7 (Blight et al., Sci. 2000, 290, 1972). Compounds are added to
dividing cultures once daily for three days. Media is changed with each
addition of compound. Cultures generally started the assay at 30-50%
confluence and reach confluence during the last day of treatment.
Intracellular HCV RNA levels and cytotoxicity are assessed 24 hours after
the last dose of compound.

[0184]Triplicate cultures for HCV RNA levels (on 48-well and 96-well
plates) and cytotoxicity (on 96-well plates) are used. A total of six
untreated control cultures, and triplicate cultures treated with
α-interferon and ribavirin can serve as positive antiviral and
toxicity controls.

[0185]Intracellular HCV RNA levels can be measured using a conventional
blot hybridization method in which HCV RNA levels are normalized to the
levels of B-actin RNA in each individual culture (Okuse et al., Antivir.
Res. 2005, 65, 23-34). Cytotoxicity is measured using a neutral red dye
uptake assay (Korba and Gerin, Antivir. Res. 1992, 19, 55). HCV RNA
levels in the treated cultures are expressed as a percentage of the mean
levels of RNA detected in untreated cultures. Representative compounds of
the invention that were tested in the above assay typically demonstrated
an IC50 of less than about 100 μm.

[0215]Compound 3 (prepared from literature procedures or from 2 by the
reaction of NCCH2P(O)(OEt)2 and sodium hydride), is reacted
with Brederick's reagent [tert-butoxybis(dimethylamino)methane] to give
4, which on acidic hydrolysis with acetic acid or trifluoroacetic acid
generates compound 5. Compound 5 is further reacted with amino
acetonitrile to give 6, where NH is protected with methoxycarbonyl and
cyclized in the presence of a base, such as DBU, and then NH is
deprotected with sodium carbonate in methanol to give desired cyclized
product 7. The isomers of the cyclized product are separated by
chromatography or crystallization. Further cyclization of desired 7 with
formamidine acetate and deprotection of the hydroxyl or amino
functionalities in R2 produces the desired targets 8.

[0216]Compound 5 is reacted with NH2CH2CO2C2H5 to
give 9, which is then cyclized with a base, such as DBU to give compound
10. The isomers of the cyclized product are separated by chromatography
or crystallization. Further cyclization of desired 10 with formamidine
acetate followed by deprotection of the hydroxyl or amino functionalities
in R2 produces the desired target 11.

[0217]Compound 5 is treated with methanesulfonyl chloride in the presence
of base and then reacted with acetylthioacetonitrile and sodium carbonate
to give compound 12, which on heating cyclizes to 13. The isomers of the
cyclized product are separated by chromatography or crystallization.
Further cyclization of desired 13 with formamidine acetate followed by
deprotection of the hydroxyl or amino functionalities in R2 produces
the desired target 14.

[0218]Compound 5 is treated with chloroacetonitrile in the presence of
potassium fluoride and 18-crown-6 to generate 15, which on treatment with
LDA cyclizes to desired 16. The isomers of the cyclized product are
separated by chromatography or crystallization. Further cyclization of
desired 16 with formamidine acetate followed by deprotection of the
hydroxyl or amino functionalities in R2 produces the desired target
17.

[0219]Compound 16 is treated with H2S gas to produce thioamide 18,
which on cyclization with formamidine acetate gives compound 19. Further
treatment of 19 with POCl3 generates protected 20, which is a common
intermediate for various R-substituted compounds. Compounds 19 and 20, if
deprotected produces the targets 20, with R═SH and Cl. Compound 19 on
treating with alkyl halides may produce S-alkyl compounds also.

[0220]Compound 20 alternatively is produced through this Scheme. The
reaction of the sodium salt of compound 5 with bromo or
chlorodiethylmalonate generates 21, which on base treatment cyclizes to
give 22. The isomers of the cyclized product are separated by
chromatography or crystallization. Further cyclization of desired 22 with
formamidine acetate gives 23, which on treatment with POCl3
generates protected 20, which is a common intermediate for various
R-substituted compounds. Compound 23, if deprotected produces the
targets, with R═OH. Compound 23 on treating with alkyl halides may
produce O-alkyl compounds also.

[0221]Compound 24 is treated with
N,N'-bis-methoxycarbonyl-5-methylthiourea in the presence of mercury (II)
chloride to generate 25, which on treatment with base for cyclization
followed by deprotection of the hydroxyl or amino functionalities in
R2 produces the desired target 26.

[0222]Compound 20, when Y═O is prepared as described in Scheme 5 and
6. When Y═S or NH, these are prepared from the corresponding 13, 7
and 18 by the same methods used in Schemes 5 and 6. Compound 20 on
treatment with i) amines, R4NH2 or R4R5NH produces
28; ii) aryl boronic acids under Suzuki coupling conditions generates 27;
iii) alkoxyamines, HNR4OR5 gives 33; iv) di-substituted
hydrazines, HNR4NHR5 produces 32; v) mono-substituted
hydrazines, NH2NHR4 gives 31; vi) thioalkoxide, R5SNa
generates 30; and vii) alkoxides, R5ONa produces 29. The hydroxyl or
amino functionalities in R2 of these compounds are deprotected under
suitable conditions to afford the appropriate targets.

Scheme 9, Preparation of Compounds of Formula I Wherein X═CH, Y═O,
NH or S, R═Cl or the Substituents as Described in Scheme 8,
R1═H, R2=any Group Described, and R3═H:

[0223]Compound 34, when Y═O is the same compound as 18 in Scheme 5.
Compound 34 when Y═NH and S, are prepared from 7 and 13 by treatment
with H2S gas. Compound 34 is converted to 35 by treating with
(CH3)2CH(CH2)2ONO and diiodomethane and iodo group of
35 is displaced with acetylenic group to generate 36 by the reaction of
trimethylsilylacetylene and (PhCN)2PdCl2 catalyst followed by
acidic treatment. Cyclization of 36 to 37 is achieved through
dimethylamine treatment in ethanol followed by aqueous acetic acid. Thio
functionality in 37 is converted to chloro with POCl3 to give 38, a
common intermediate. Further treatment of 38 with the reagents described
in Scheme 8 followed by deprotection of amino and hydroxyl groups in
R2 yields the desired targets 38, where Cl is replaced by different
groups.

[0224]Compounds can also be prepared as illustrated in the following
Schemes A-1 to D-2.

[0225]Preparation of R2--CH2CN Compounds:

##STR00024##

Preparation of Compounds of the Invention from R2CH2CN
Intermediates

[0226]In the following schemes, R2 is a sugar group bearing one or
more protecting groups.

##STR00025##

##STR00026##

##STR00027##

[0227]Deprotection of protecting groups in R2 gives the target
molecules

##STR00028##

##STR00029##

##STR00030##

##STR00031##

##STR00032##

[0227]Preparation of Monophosphates and Triphosphates of Nucleosides
(Represented by Example C-1)

[0228]The following Schemes illustrate the preparation of compounds of
formula I that have one or more phosphate groups. In these Schemes, B
represents the furopyrimidine base of formula I, and B(P) represents the
furopyrimidine base of formula I, bearing one or more protecting groups.

##STR00033##

##STR00034##

[0229]B and R are the same as in Scheme C-1

Preparation of Prodrugs

[0230]The following Schemes illustrate the preparation of prodrugs of the
invention.

##STR00035##

[0231]B and R are the same as in scheme C-1 [0232]R'=aminoacid ester

##STR00036##

[0233]B and R are the same as in scheme C-1 [0234]R'═CH3,
C(CH3)3

[0235]The invention will now be illustrated by the following non-limiting
Examples.

[0237]Step 1: To a solution of D-ribose (61 g, 406.66 mmol) in methanol (1
L) was added conc. sulfuric acid (6.1 mL) and stirred at 4° C. for
16 h. The reaction mixture was neutralized using triethylamine (40 mL),
concentrated to dryness and co-distilled twice with 200 mL of toluene to
remove trace amount of water. This furnished 72 g of crude
O-methyl-D-ribofuranose, which was used as such for next step.

[0240]Step 4: To a stirred solution of product from Step 3 (15 g, 35.67
mmol) in THF (150 mL) was added diethyl (cyanomethyl)phosphonate (6.95 g,
39.23 mmol) at room temperature followed by lithium
bis(trimethylsilyl)amide (39.2 mL, 1M solution in THF) addition at
-78° C. The reaction mixture was stirred at -78° C. for
about 20 min and at 0° C. for 1.5 h and then was quenched by
adding water (50 mL). The reaction was extracted with ether (2×200
mL), washed with water (2×50 mL), brine (1×50 mL), and dried
over MgSO4. After filtration, the filtrate was concentrated and
purified by flash chromatography using 0 to 30% ethyl acetate in hexanes
to give 10.79 g (68.2%) of desired compound as a mixture of isomers as an
oil. MS (ES.sup.+) 444.33 (M+1).

[0242]Step 1: To a stirred solution of compound from Step 4 of example
A-1, (3S,4R,5R)-(3,4-bis-benzyloxy-5-benzyloxymethyl-tetrahydro-furan-2-y-
l)-acetonitrile (10.7 g, 24.12 mmol) in DMF (150 mL) was added
tert-butoxybis(dimethylamino)methane (21.02 g, 120.62 mmol) at room
temperature and stirred for 12 h. The reaction mixture was diluted with
toluene (700 mL) and washed with water (2×250 mL), brine
(1×50 mL) and dried (MgSO4). After filtration, the filtrate
was concentrated to give (13.8 g) of desired product, which was used as
such for next step.

[0244]Step 3: To a stirred solution of product from Step 2, (186.5 g,
395.4 mmol) in DMF (1500 mL) was added sodium hydride (19.7 g, 60%, 494.3
mmol) in four portions at 0° C. over a period of 1.5 h followed by
2-bromodiethylmalonate (118.1 g, 494.3 mmol) over a period of 30 min at
0° C. and stirred at room temperature for 12 h. After diluting
with water (1000 mL), the reaction mixture was extracted with ethyl
acetate (3×2000 mL). The combined organic extracts were washed with
water (2×1000 mL), brine (1×200 mL), and dried (MgSO4).
After filtration, the filtrate was concentrated to give 296 g of crude
desired product, which was used in the next reaction without further
purification.

[0245]Step 4: To a compound from Step 3 (296 g, crude) in EtOH (1000 mL)
was added 1,5-diazabicyclo[4.3.0]non-5-ene (58.9 g, 474.48 mmol) at room
temperature and stirred for 18 h. The reaction mixture was concentrated
and the residue was dissolved in ethyl acetate (4000 mL), washed with
water (2×1000 mL), brine (2×500 mL), and dried (MgSO4).
After filtration, the filtrate was concentrated and the crude residue was
purified by flash chromatography on silica gel using ethyl acetate and
hexanes to afford 29 g, (13.1%) of the desired product as light brown
oil.

[0249]Step 1: A solution of chloro compound from example B-2 (1 equiv.),
appropriate amine (6 equiv.), and triethylamine (20 equiv.) in ethanol
was heated at 35 to 45° C. for 5 h to 15 h. After concentration,
the residue was partitioned between chloroform or ethyl acetate and
water. The organic layer was washed with water and brine, dried over
MgSO4. After filtration the residue was purified by crystallization
or on silica gel column using appropriate solvent system.

[0250]Step 2: A solution of product from step 1 (1 equiv.) in
dichloromethane was treated with 1M solution of BCl3 in
dichloromethane (2 to 10 equiv.) at 0 to -78° C. and stirred for
1-3 h. The reaction mixture was quenched with methanol and concentrated
to dryness. The residue was co-evaporated with HCl and ethanol mixture
two times and with ethanol two times. The residue was purified by
re-crystallization or silica gel column using appropriate solvent system.

[0294]Step 1: To a solution of product from step 4 of example B-1 (0.49 g,
0.88 mmol) in pyridine (10 mL) was added triethylamine (0.62 mL, 4.4
mmol), mercury (II) chloride (0.48 g, 1.76 mmol), 1,3
dicarbomethoxy-2-methyl-2-thiopsuedourea (0.37 g, 1.76 mmol) and the
reaction mixture was stirred at 50° C. overnight. Reaction was not
complete so the same amounts of the reagents were added again and heated
at 50° C. for 48 h. Solvent was removed under vacuum and the
residue was triturated with ethyl acetate (100 mL) and filtered through a
pad of Celite® to remove insoluble impurities. The filtrate was
concentrated under vacuum and the residue obtained was purified by column
chromatography (silica gel 40 g, eluting with 0-75% ethyl acetate in
hexanes) to furnish the desired product as yellow oil. It was used as
such for the next step

[0296]Step 3: To the product from Step 2 (60 mg, 0.1 mmol) in methanol
(1.0 mL) was added 1N NaOH (0.25 mL, 0.25 mmol) and heated at RT
overnight. Again 1N NaOH (0.75 mL) was added and heated at 50° C.
for 4 h. The reaction mixture was cooled to room temperature and pH
adjusted to 6 using glacial acetic acid. The reaction mixture was
concentrated under vacuum to remove methanol and the residue was purified
on a column of silica gel to give 41 mg of desired product.

[0298]Triphosphate of
4-methylamino-7-β-(D-ribofuranosyl)-furo[3,2-d]pyrimidine

[0299]Step 1: A mixture of compound from example B-3 (66 mg, 0.23 mmol),
MMTrCl (87 mg, 98%, 0.28 mmol), DMAP (5 mg, 0.04 mmol), and pyridine
(2.25 mL) in DMF (1.5 mL) was stirred at room temperature for 22 h.
Additional three portions of MMTrCl (87 mg, 180 mg, 180 mg) were added
and the reaction mixture was stirred for 15 h, 23 h, and 45 h,
respectively after each addition of MMTrCl. The reaction mixture was then
treated with triethylamine (1.7 mL, 12.2 mmol), DMAP (14 mg, 0.11 mmol),
and 4-nitrobenzoyl chloride (0.87 g, 98%, 4.59 mmol) and stirred at room
temperature for 67 h followed by dilution with ethyl acetate (100 mL).
After washing with water (2×50 mL) and brine (50 mL), the organic
phase was dried over MgSO4, filtered and the filtrate was
concentrated. The residue was purified on a silica gel column using
hexanes/EtOAc (1:0 to 1:1) as eluent to give crude product (269 mg),
which was use as such for the next step.

[0300]Step 2: A solution of the above product from step 1 (260 mg) in
acetonitrile (8 mL) was treated with 0.2 N HCl (0.4 mL) and stirred at
room temperature for 3 h. The reaction mixture was brought to pH 5 with
0.5 N aq. NaOH followed by dilution with water (20 mL) and concentration
to remove most of acetonitrile. The aqueous mixture was extracted with
EtOAc (2×25 mL) and chloroform (2×50 mL). The combined
extracts were dried over MgSO4. After filtration and concentration,
the residue was purified twice on a silica gel column using
hexanes/EtOAc/MeOH (1:0:0 to 1:1:0.1) as eluent to give product (47 mg,
˜90% pure) which was used as such for next step. MS (ES.sup.-):
727.65 (M-1).

[0301]Step 3: A suspension of the above product from step 2 (45 mg) in a
mixture of pyridine (70 μL) and 1,4-dioxane (210 μL) was treated
with a freshly prepared solution of
chloro-4H-1,3,2-benzodioxaphosphorin-4-one (1M in 1,4-dioxane, 75 μL).
The reaction mixture was stirred at room temperature for 20 min followed
by treatment with a solution of tributylammonium pyrophosphate, 1.6
Bu3N.1.0H4P2O7 (47 mg, 0.10 mmol) in DMF (205 μL)
and tri-n-butylamine (65 μL), simultaneously. The clear solution
formed was stirred at room temperature for 30 min followed by treatment
with 2.6 mL of 1% I2 in Py/H2O (98/2). Excess iodine was
reduced by 5% aqueous sodium thiosulphate (215 μL) and the resulting
solution was concentrated to dryness. The residue was treated with conc.
NH4OH (20 mL). The reaction mixture was stirred at room temperature
overnight followed by concentration to dryness. The residue was dissolved
in H2O (20 mL) and washed with CH2Cl2 (2×15 mL). The
aqueous phase was concentrated under vacuum for a short period of time to
remove the trace amounts of CH2Cl2 and purified by DEAE ion
exchange column chromatography with a linear gradient of TEAB buffer (1M
TEAB buffer, pH=8.0/H2O, 250 mL/250 mL, 0:1 to 1:0). The fractions
containing the desired nucleotide was combined and concentrated. The
residue was redissolved in H2O and purified further by HPLC
(CH3CN/0.1 M TEAB buffer, pH=8.0, 0-20 min, 0-35% CH3CN; 20-28
min, 35-100% CH3CN, monitoring at 260 nm) to give desired
triphosphate (tR=15.3 min). 1H NMR (D2O): δ 8.17 (s,
1H), 8.04 (s, 1H), 5.00 (d, J=6.0 Hz, 1H), 4.40-4.00 (m, 5H), 2.94 (s,
3H); 31P NMR (D2O): δ -6.28 (1P), -9.70 (1P), -20.47
(1P); MS (ES.sup.-): 520.14 (M-1).

Example D-1

[0302]The following illustrate representative pharmaceutical dosage forms,
containing a compound of formula I, or a pharmaceutically acceptable salt
or prodrug thereof (`Compound X`), for therapeutic or prophylactic use in
humans.

The above formulations may be obtained by conventional procedures well
known in the pharmaceutical art.

[0303]All publications, patents, and patent documents are incorporated by
reference herein, as though individually incorporated by reference. The
invention has been described with reference to various specific and
preferred embodiments and techniques. However, it should be understood
that many variations and modifications may be made while remaining within
the spirit and scope of the invention.